Description du projet
Une régulation collective des cellules souches hématopoïétiques
Les cellules souches hématopoïétiques (CSH) contribuent à la production des cellules sanguines tout au long de la vie et sont présentes dans la moelle osseuse des personnes adultes. À l’âge adulte, la vaste majorité des CSH passent de manière synchrone à un état de repos et quelques‑unes d’entre elles se retrouvent dans les étapes actives du cycle cellulaire qui compense la perte des CSH basales du fait de la différenciation ou de la mort cellulaire. Le projet IC-CCD-qHSC, financé par l’UE, entend tester la théorie selon laquelle l’interaction moléculaire entre les CSH proximales leur permet de percevoir leurs densités locales et déclenche la régulation collective de la fonction des CSH dans le but de préserver l’homéostasie. Les objectifs consistent à caractériser les composantes anatomiques et fonctionnelles des dépendances spatiales entre les CSH, étudier les mécanismes de détection du quorum des interactions entre les CSH et étudier la potentielle concurrence pour les ressources moléculaires situées dans les régions cellulaires voisines à l’échelle locale.
Objectif
Hematopoietic stem cells (HSCs) contribute to blood cell production throughout life and are found at rare, yet tightly regulated frequencies in adult bone marrow (BM). During embryonic and postnatal development, HSCs expand through continuous self-renewing proliferation. Upon entry into adulthood the vast majority of HSCs synchronously convert to a quiescent state. From then on, at any given moment very few HSCs are found in active stages of cell cycle, which suffices to compensate basal HSC loss due to differentiation or cell death. Since proliferation rates of individual HSCs are heterogeneous, entry and exit from cell cycle need to be coordinated at the level of the HSC pool. To date, the mechanisms that orchestrate this collective proliferative behavior and effectively control the maintenance of homeostatic HSC numbers remain unknown. In preliminary work for this project we have customized a pipeline that combines 3D microscopy, deep learning-based image analysis and spatial statistics. Using these tools, we observed that despite showing broad spatial heterogeneity, HSCs tend to cluster and accumulate in relatively large regions of the BM. We now postulate that molecular crosstalk between proximal HSCs enables them to perceive their local densities and triggers collective regulation of HSC function to preserve homeostasis. Through a multidisciplinary approach involving high-level microscopy, spatial analyses, comprehensive metabolomic profiling and single-cell transcriptomics we aim to 1) characterize the basic anatomical and functional features of spatial dependencies between HSCs 2) study the potential role of quorum-sensing mechanisms in HSC crosstalk and 3) investigate if competition for molecular resources in local neighborhoods contributes to maintenance of HSC homeostasis. Our research has the potential to unravel novel complex forms of cellular interplay and substantially advance our understanding of hematopoietic tissue organization.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
8006 Zurich
Suisse